Our overall objective is to study biochemical and genetic predictors of atherogenesis in youth. We will explore this objective in multiple generations of 61 large families (average size 19.8) previously ascertained through male and female probands with (N=32) and without (N=29) angiographically documented premature coronary artery disease (CAD). Traditional and non-traditional risk factors for CAD will be compared in relatives of the probands (211 children, 157 sibs, 189 grandchildren, 427 nieces and nephews). These risk factors include plasma levels of total, VLDL, LDL, HDL, HDL2 and HDL3 cholesterol, triglycerides, Lp(a), apoB, apoAI, lipoprotein particles (ApoAI only and LpCIII B and nonB), glucose, and insulin; Lp(a) polyforms and apoE isoforms; blood pressure, obesity, and cigarette smoking. Differences in the expression of these risk factors over time between children, adolescent young adults and adults will be studied. The heritability and penetrance of these traditional and non-traditional risk factors will be determined by segregation analysis; the influence of candidate genes, such as the lipoprotein lipase gene, on these risk factors and other metabolic and cellular abnormalities will be determined by linkage analysis; we will also look for specific mutations which may further explain these relationships. We will determine whether there are differences in endothelial cell function, as judged by high resolution ultrasound, in the relatives of the probands and examine which traditional and non-traditional risk factors best predict endothelial cell dysfunction. The biochemical expression of acylation stimulatory defects with the human serum basic proteins in cultured fibroblasts will be studied in several groups including: 1) CAD(-) proband, normal lipoprotein phenotype (N=6); 2 CAD(+) probands with hyperapoB and increased triglycerides (N=5); 3) CAD(+) probands with hyperapoB and normal triglycerides (N=6); 4) CAD(+) probands with type IV (N=6); and, 5) CAD(+) probands with normal lipoprotein phenotype (N=6). The concordance between the cellular defect and the presence of dyslipidemia, small, dense LDL, and CAD will be determined. In a subset of families, selected by probands with and without cellular acylation stimulatory defect, we will test the hypothesis that the defect is transmitted as a Mendelian dominant in the children and grandchildren of the probands. Our integrated hypothesis is that there is a cellular defect in a substantial proportion of families who develop CAD that is responsible for the pleiotropic phenotype of hyperapoB (and related syndromes), and furthermore, that this cellular defect is reflected in the expression of other risk factors that will accompany the syndrome.